CN1163491C - 3-amino-2-mercapto phenyl formic acid erivative and its preparation - Google Patents
3-amino-2-mercapto phenyl formic acid erivative and its preparation Download PDFInfo
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Abstract
Compounds of the formula I and disulfides thereof and salts thereof are important intermediate products for the preparation of compounds having a microbicidal and plant-immunizing action. Processes for the preparation of compounds of the formula I are described.
Description
The application is to be dividing an application of December 20, denomination of invention in 1996 Chinese patent application 96117901.5 that is 3-amino-2-mercapto phenyl formic acid erivative and method for making thereof the applying date.
The present invention relates to formula I compound:
And disulphide and salt thereof with and preparation method thereof and it be used to prepare formula III application of compound with microbicidel and plant immunization effect:
In formula I and III compound:
X is a halogen,
N is 0,1,2 or 3;
Z is CN, CO-A or CS-A,
A is hydrogen, OR
1, SR
2And N (R
3) R
4
R
1To R
4Be hydrogen, contain the replacement that is no more than 8 carbon atoms or non-replacement open chain is saturated or unsaturated alkyl, contain the replacement that is no more than 10 carbon atoms or non-substituted cyclic is saturated or unsaturated alkyl, replacement or non-substituted benzyl or styroyl, contain the replacement or non-replacement alkyloyl, replacement or non-substituted benzoyl or replacement or the non-substituted heterocyclic radical that are no more than 8 carbon atoms; Or R
3With R
4Together with the nitrogen-atoms with their keys company is 5-or 6-person's replacement with 1-3 heteroatoms O, S and/or N or non-substituted heterocyclic radical.
The compound of this formula I has at least one basic group, thereby can form acid salt.As with such as mineral acids such as sulfuric acid, phosphoric acid or haloid acid, with such as organic carboxyl acids such as acetate or oxalic acid, propanedioic acid, toxilic acid, fumaric acid or phthalic acid, with such as hydroxycarboxylic acid such as xitix, lactic acid, oxysuccinic acid, tartrate or citric acid or with form these acid salt such as organic sulfonic acid such as methylsulfonic acid or right-toluenesulphonic acids.
Based on SH base or the acidic group among the substituting group Z, formula I compound also can form salt with alkali.Suitable alkali salt is such as metal-salt such as basic metal or alkaline earth salt, as sodium, potassium or magnesium salts, or with the salt of ammonia or organic amine, as morpholine, piperidines, tetramethyleneimine,, two or the trihydroxy-low-grade alkylamine as one, two or the salt of trolamine.If suitable, also can form corresponding inner salt.
Unless otherwise defined, provide the implication of general terms used herein below: alkyl can be saturated or undersaturated, open chain or cyclic or open chain and cyclic mixture such as cyclopropyl methyl or benzyl.
Alkyl is straight chain or branching, depends on their carbonatoms, for example is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, sec.-amyl sec-pentyl secondary amyl, tert-pentyl, 1-hexyl or 3-hexyl.
Unsaturated alkyl is alkenyl, alkynyl or alkenyl alkynyl, and at least 3 kinds of multiple bonds are arranged, as butadienyl, hexatriene base, 2-amylene-4-alkynes.
Alkenyl can be regarded as expression straight chain or branched chain thiazolinyl, as allyl group, methacrylic, 1-methyl ethylene or but-2-ene-1-base.Preferably have the alkenyl that chain length is 3～4 carbon atoms.
Alkynyl can be straight chain or branching equally, depends on its carbonatoms, as propargyl, fourth-1-alkynes-1-base and fourth-1-alkynes-3-base.Propargyl preferably.
Unsaturated cyclic hydrocarbon radical can be aromatics such as phenyl and naphthyl, or non--aromatics, as cyclopentenyl, cycloheptenyl and cyclooctadiene base, or partially aromatic, as tetralyl and indanyl.
Halogen or halo and Hal are fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Haloalkyl can contain identical or different halogen atom, as methyl fluoride, difluoromethyl, difluoro chloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoro ethyl, 2-chloroethyl, 2,2,2-three chloroethyls and 3,3, the 3-trifluoro propyl.
Alkoxyl group is for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and uncle's oxygen base; Preferred methoxyl group and oxyethyl group.
Halogenated alkoxy is for example difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2-fluorine oxyethyl group and 2,2-difluoroethoxy.
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkyloyl is straight chain or branching.Example has formyl radical, ethanoyl, propionyl, butyryl radicals, pivaloyl group or capryloyl.
Heterocyclic radical can be regarded as heteroatomic 5-or 6-person's aromatics and the non-aromatic ring that expression contains N, O and/or S.Replace or the benzo base of non-replacement also can with this molecule rest part mutually bonding such heterocyclic group condense mutually.The example of heterocyclic radical has pyridyl, pyrimidyl, imidazolyl, thiazolyl, 1,3, and the 4-thiadiazolyl group (1,3,4-thiadiazolyl), triazolyl, thienyl, furyl, pyrryl, morpholinyl, oxazolyl and corresponding partly or entirely hydrogenation ring.The example that has the heterocyclic group that condenses the benzo base has quinolyl, isoquinolyl, benzoxazolyl, quinoxalinyl, benzothiazolyl, benzimidazolyl-, indyl and indolinyl.
Formula III compound and manufacture method thereof with microbicidel and plant immunization effect are known, as see EP-A-313,512.Wherein said method is not suitable for industrial preparation, because this must have a lot of reactions steps, some of them are very complicated, and finally cause underproduce.
Therefore require the new industrial more advanced method of synthetic these compounds.
And the compound of general formula I of the present invention makes a kind of approach of new acquisition formula III compound become possibility, and this approach is seen expression formula 1.This synthetic method even under the situation of not separating intermediate product, all have precursor easy to operate, only use the high characteristics of popular response agent and productive rate.
The present invention also relates to this synthetic method.
In expression formula 1 various,
X, n and Z define the definition suc as formula I,
T is hydrogen, C
1-C
12Alkyl, especially C
1-C
6Alkyl, C
3-C
6Alkenyl, C
3-C
6Alkynyl, C
3-C
6Cycloalkyl or replacement or non-substituted-phenyl, benzyl or styroyl.
The precursor of formula V is that industrial obtainable compound maybe can be by currently known methods as reducing the compound of method preparation of corresponding nitrogen compound.
Expression formula 1
More detailed theory, this reactions steps can be carried out as follows:
(1) SCN-T as Trapex/inert solvent, can have acid or alkali to exist as needs; Or SCN salt.
(2) oxygenant is as SO
2Cl
2Or Br
2Or H
2SO
4/ bromide or Cl
2
(3) strong alkali aqueous solution is as potassium hydroxide solution, preferably under inert atmosphere.
Said reaction (1), (2) and (3) for example are found in:
Org.Synthesis，Coll.Volume?III，page?76；
J.Het.Chem.Volume?17，page?1325，(1980)；
US-5,374,737；
Ukrain.Khim.Zhur.Volume 22,363, and 1956; Select from chemical abstracts 22,4358b, (1957).
(3a) diazotization/H
3PO
2(Synth.Comm.Volume 10, and page 167 1980)
(4) diazotization and cyclisation, as with nitrous acid (=HONO) or with a kind of inorganic or organic nitrite, as Sodium Nitrite or Isopentyl nitrite (as EP-A-313,512).
(4a) as the method for hydrolysis of hydrazine/ethanol or alkali, or as 4) (Synth.Comm.Volume10, page 167 1980).
(4b) as Zn/ acid or Fe/ acid (" heterogeneous ring compound ", Volume 7, page 541 et seq.); Or H
2/ catalyzer.
(5) the COOH group can be undertaken by currently known methods to the method for transformation of Z group, and shown in expression formula 3, wherein the Z definition is suc as formula I.
Preferred formula I compound is:
(1) the following compound of each group:
X is a fluorine;
N is 0,1,2 or 3;
Z is CN, CO-A or CS-A,
A is OR
1, SR
2Or N (R
3) R
4And wherein
R
1, R
2And R
3Be hydrogen, C
1-C
8Alkyl is non-replacement or by 1-5 halogen atom, C
3-C
6Cycloalkyl, C
1-C
4Alkoxyl group, phenoxy group, benzyloxy C
1-C
4Acyloxy, benzoyloxy, hydroxyl, nitro, cyano group, C
1-C
4Alkyloyl, benzoyl, carboxyl, C
1-C
4Alkoxy carbonyl, benzyloxycarbonyl, amino, C
1-C
4Alkylamino, C
1-C
4That dialkyl amido or heterocyclic radical replace, C
3-C
6Alkenyl, be non-replacement or replaced by 1-5 halogen atom, C
3-C
6Alkynyl, C
3-C
6Cycloalkyl, C
1-C
4Alkyloyl, phenyl, benzyl or styroyl, each phenyl ring are that non-replacement or one to three time are by halogen, hydroxyl, C
1-C
4Alkyl, halo-C
1-C
2Alkyl, C
1-C
2Alkoxyl group, halo-C
1-C
2That alkoxyl group or nitro replace or naphthyl, benzoyl or heterocyclic radical, this heterocyclic radical be non-replacement or once to three times with identical or different method by halogen, C
1-C
2Alkyl, halogenated methyl or nitro replace, or
R
4Be hydrogen, C
1-C
6Alkyl, phenyl or benzyl; Or
R
3And R
4With the nitrogen-atoms that connects together with their keys is to have the 5-of 1-2 heteroatoms O, S and/or N or 6-person's ring, this ring be non-replacement once or secondary with identical or different method by halogen, C
1-C
3Alkyl or C
1-C
2Alkoxy carbonyl replaces.
(2) the following compound of its each group:
X is a fluorine;
N is 0 or 1;
Z is CN or CO-A,
A is OR
1, SR
2Or N (R
3) R
4
(3) the following compound of each group:
X is a fluorine;
N is 0 or 1;
Z is CN or CO-A,
A is OR
1, or SR
2With
R
1And R
2Be hydrogen, C
1-C
6Alkyl is non-replacement or by 1-3 halogen atom, C
3-C
6Cycloalkyl or C
1-C
2That alkoxyl group replaces, C
3-C
4Alkenyl, be non-replacement or replaced by 1-3 halogen atom, C
3-C
4Alkynyl, C
3-C
6Cycloalkyl or phenyl, benzyl or styroyl, each phenyl ring be non-replacement once or secondary by halogen, hydroxyl, C
1-C
4Alkyl, halo-C
1-C
2Alkyl, C
1-C
2Alkoxyl group, halo-C
1-C
2Alkoxyl group or nitro replace.
(4) compound of formula Ial or its disulphide or its salt
According to other method, the compound of formula I can be according to expression formula 2 by corresponding benzo dithiazole salt VI or hydroxy benzo dithiazole VII preparation (Houben-Weyl, E 8d, Het-eroarene (Heteroarenes) III, Part4; Page 2et seq. and page 59et seq.).
Expression formula 2
(a) sulfur halide is as S
2Cl
2Or SCl
2(anils V first-selection is changed into corresponding hydrochloride) is at 0-120 ℃ of following inert solvent, in acetate.(J.Org.Chem.30，2763，J.Het.Chem，3，518，ibid?5，1149)
(b1) H
2O or H
2O/NaOAc (0-50 ℃) (Khim.Get.Soed. (9), 1205 (1979); Synth.Comm.
23, 263)
(b2) H
2O/20-100 ℃ is added with or does not add alkali, as sodium bicarbonate, and yellow soda ash or dilution basic metal or alkaline earth metal hydroxides or oxide compound (J.Am.Chem.Soc.68,1594 (1946)).
(c) dihalide sulphur is (as SCl
2), thionylhalides (SOCl
2)-20-100 ℃ (J.Het.Chem.3,518),
(d) S (O) L
2, wherein L is a leavings group, as halogen, imidazoles-1 '-Ji or 1,2, the 4-triazol-1-yl is as thionyl diimidazole or SOCl
2,-30-100 ℃, inert solvent (J.Org.Chem.30,2763 (1965)).
Benzo dithiazole salt VI also can need not separate under the condition that is fit to VII, further reaction in (J.Chem.Soc, 1970,2250, Houben Weyl E8d, Heteroarene (Het-eroarenes) III, Part 4, page 59et seq. (specifically page 93et seq.)), to obtain diazosulfide III or IIIa.
The method for transformation of expression formula 3:Z group
(a) chlorizating agent is as SOCl
2Or COCl
2
(b) M-A (III), wherein M is hydrogen, Li
+, Na
+, K
+, 1/2Mg
2+Or quaternary ammonium ion, A defines suc as formula I;
(c) thiosulfuric acid agent, as thiophosphoric anhydride or 4-p-methoxy-phenyl phosphine sulfide acid epidithio for acid anhydrides (" Lawesson ' s reagent ");
(d)NH
3；
(e) dewatering agent is as SOCl
2Or COCl
2
(f) reduction, as usefulness hydrogen/catalyzer, or with cooperating hydride, as LiAlH
2(OCH
2CH
2OCH
3)
2
By currently known methods own, as do not have or be under the situation that is added with suitable solvent or thinner or their mixture, to carry out these reactions, as required, can be under cooling, room temperature or heating condition, as making an appointment with-80 ℃ to the boiling spread of reaction medium, be preferably approximately and react under-20 ℃ of extremely about+170 ℃ of temperature, if desired, can in an encloses container, under pressure, in inert atmosphere and/or under anhydrous condition, react.
Diazotization reaction, promptly primary amine and nitrous acid or with the reaction of an inorganic or organic nitrite to be advisable at-20 ℃ to+30 ℃.
Leavings group for example is fluorine, chlorine, bromine, iodine, C
1-C
8Alkylthio is as methylthio group, ethylmercapto group or rosickyite base, C
1-C
8Alkanoyloxy is as acetoxyl group, (halo)-C
1-C
8Alkylsulfonyloxy, as mesyloxy, ethanesulfonyloxy group or trifluoro-methanesulfonyl oxy or replacement or non-substituted phenyl sulfonyl oxygen base, as phenylsulfonyloxy or tolysulfonyl oxygen base, imidazolyl, triazolyl, hydroxyl or water, preferred chlorine, bromine, iodine and tolysulfonyl oxygen base.
The alkali that is suitable for for example has basic metal or alkaline earth metal hydroxides, hydride, acid amides, alkane alkoxide, carbonate, dialkyl amide or the saturated or unsaturated cycloalkanes amine of alkyl silicomethane acid amides, alkylamine, Alkylenediamine, non-alkylation or N-alkylation, alkaline heterogeneous ring compound, ammonium hydroxide and carbocyclic amines.The example has oxyhydroxide, hydride, acid amides, sodium methylate and the yellow soda ash of sodium, potassium tert.-butoxide and salt of wormwood, diisopropyl amide lithium, two (trimethyl silyl) acid amides potassium, hydrolith, triethylamine, triethylenediamine, hexahydroaniline, N-cyclohexyl-N, N dimethylamine, N, N-Diethyl Aniline, pyridine, 4-(N, the N-dimethylamino) pyridine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo (5.4.0)-11 carbon-5-alkene (DBU).
This reagent can directly react to each other, and promptly need not to add solvent or thinner, but for example with melt form.But it generally is favourable adding inert solvent or thinner or their mixture.The example of these solvents or thinner is aromatic hydrocarbons, aliphatic hydrocrbon and alicyclic hydrocarbon and halon, as benzene,toluene,xylene, chlorobenzene, bromobenzene, sherwood oil, hexane, hexanaphthene, methylene dichloride, chloroform, ethylene dichloride or trichloroethane; Ethers such as ether, t-butyl methyl ether, tetrahydrofuran (THF) or dioxan; Ketone is as acetone or methylethylketone; Alcohols such as methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol or glycerol, ester class such as ethyl acetate or butylacetate; Acid amides, as N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or hexamethyl phosphoric triamide; Nitrile is as acetonitrile; As sulfoxide, as dimethyl sulfoxide (DMSO).Used excessive bases such as triethylamine, pyridine, N-methylmorpholine or N, the N-Diethyl Aniline also can be used as solvent or thinner.This reaction also can be carried out in the presence of alkaline aqueous solution such as sodium hydroxide and phase-transfer catalyst such as hydrogen sulfate TBuA in organic solvent such as methylene dichloride or toluene by phase transfer catalysis process.
Typical reaction conditions is seen embodiment.
The invention still further relates to following preparation method, wherein in general formula described in (1) to (6) item, substituting group defines the relevant definition as expression formula I:
(1) preparation method of compound of Formula I or its salt,
This method comprises makes formula II compound and highly basic aqueous fluid reaction, obtains the compound or its salt of formula Ia, further obtains formula I compound with this product reaction.
(2) preparation method of general formula I a compound or its salt,
This method comprises makes formula II compound and highly basic aqueous fluid reaction, especially reacts under 120-150 ℃ of temperature and 1-5 bar pressure with potassium hydroxide or sodium hydroxide solution.
(3) prepare the method for formula III compound
This method comprises:
(a) make the reaction of formula II compound and highly basic aqueous fluid, obtain a kind of formula Ia compound or its salt and if desired, or
(b1) carry out diazotization reaction and as required product is changed into the formula III compound with nitrous acid or organic or inorganic nitrite; Or
(b2) this product is changed into formula I compound and change it into formula III compound by carrying out diazotization reaction with a nitrous acid or an organic or inorganic nitrite.
(4) preparation method of formula III a compound:
This method comprises that making formula II compound obtain formula Ia compound or its salt with highly basic aqueous fluid reaction separates with need not, by carrying out the compound that diazotization reaction directly changes it into formula III a with a nitrous acid or an organic or inorganic nitrite; Wherein especially the first step is reflected under 120-170 ℃ and the 1-5 bar pressure and carries out in potassium hydroxide solution, and wherein carries out diazotization reaction with Sodium Nitrite.
(5) preparation method of formula I compound,
This method is included in hydrolyzing type VI compound under neutrality or the alkaline condition.
(6) preparation method of formula II compound or its salt:
If being included in to make formula V compound and SCN-T in a kind of solvent or be suitably in acid or alkali with SCN salt, this method reacts under existing, and with the formula IV compound and oxygenant such as the SO that are obtained
2Cl
2Or Br
2Or H
2SO
4/ bromide or Cl
2Reaction obtains formula II compound.
Preferably in the first step reaction, use C
1-C
6Alkyl lsothiocyanates, especially Trapex; The solvent that is fit to is the anhydrous carboxylic acid, as formic acid and acetate; Pure as ethanol and Virahol, ketone, ethers and halon.
Particularly preferably in same solvent as in acetate, carrying out this two-step reaction and not needing separate type IV compound.
The invention still further relates to the new intermediate of Formula Il, IV and VI or their salt:
In the formula:
X is a halogen,
N is 0,1,2 or 3;
T is hydrogen, C
1-C
6Alkyl, C
3-C
6Alkenyl, C
3-C
6Alkynyl, C
3-C
6The phenyl of cycloalkyl or replacement or non-replacement, benzyl or styroyl; Z is CN, CO-A or CS-A,
A is hydrogen, halogen, OR
1, SR
2And N (R
3) R
4
R
1To R
4Be hydrogen, contain the replacement that is no more than 8 carbon atoms or non-replacement open chain is saturated or unsaturated alkyl, contain and be no more than that 10 carbon atoms replace or non-substituted cyclic is saturated or unsaturated alkyl, replacement or non-substituted benzyl or styroyl, contain the replacement that is no more than 8 carbon atoms or alkyloyl, replacement or non-substituted benzoyl or the replacement or the non-substituted heterocyclic radical of non-replacement; Or
R
3And R
4Together with the nitrogen-atoms with their keys company is replacement or the non-substituted heterocyclic radical that 5-or 6-person have 1-3 heteroatoms O, S and/or N; With
Hal is halogen, ClO
4Or BF
4
But do not comprise Compound I I and IV, Z is COOC in the formula
2H
5, n be 0 and T be that hydrogen is (at Ukrain.Khim.Zhur.Volume 22,363, known in 1956; Select from Chem.Abstr.22,4358b, 1957),
And compound VI, wherein Z is COOCH
3Be 0 with n (at J.Chem.Soc.1970, known in 2250, separate and characterize but give).
Preferred formula II, IV and VI compound that wherein each group definition is following:
X is a fluorine;
N is 0 or 1;
T is hydrogen or C
1-C
6Alkyl;
Z is CN or CO-A,
A is OR
1, SR
2Or N (R
3) R
4And wherein
R
1To R
4Same definition;
Among these, those compounds that especially are defined as follows:
A is OR
1Or SR
2And
R
1And R
2Be hydrogen, C
1-C
6Alkyl, this alkyl are non-replacements or are replaced C by 1-3 halogen atom
3-C
6Cycloalkyl, or C
1-C
2Alkoxyl group, C
3-C
4Alkenyl, for non-replacement or replaced by 1-3 halogen atom, C
3-C
4Alkynyl, C
3-C
6Cycloalkyl or phenyl, benzyl or styroyl, its phenyl ring be non-replacement or once or twice by halogen, hydroxyl, C
1-C
4Alkyl, halo-C
1-C
2Alkyl, C
1-C
2Alkoxyl group, halo-C
1-C
2Alkoxyl group or nitro replace; Among these, special following those compounds of group of preferred definition, wherein n is 0
T is hydrogen or methyl;
Z is CO-A,
A is OR
1With
R
1Be hydrogen, C
1-C
6Alkyl, this alkyl be non-replacement or replaced or C by 1-3 halogen atom
1-C
2Alkoxyl group, C
3-C
6Cycloalkyl or phenyl, benzyl or styroyl, its phenyl ring are non-replacements, or once or twice by halogen, hydroxyl, C
1-C
4Alkyl, halogen-C
1-C
2Alkyl, C
1-C
2Alkoxyl group, halogen-C
1-C
2Alkoxyl group or nitro replace.
Hal is preferably chlorine in formula VI compound.
Preparation embodiment:
Embodiment 1:3-amino-2-mercapto phenyl formic-phenylformic acid (Ia1)
Under nitrogen atmosphere stir and with ice-cooled making in temperature be no more than in 25 ℃ in 20 minutes and restrain 2-amino-benzothiazole-7-carboxylate methyl esters to 3.5 and in the solution of 38 milliliters of dioxan, drip and be dissolved in 28.9 in 38 ml waters and restrain potassium hydroxide (85%).Thereafter bathing 140 ℃ of temperature this mixtures that reflux down, finish up to this reaction, interior temperature increases to 170 ℃ and distill out dioxan with the downstriker condenser, then this mixture is cooled to 0 ℃ and filter under nitrogen atmosphere, and with 30 milliliters of frozen water rinsing resistatess.By being acidified in addition cooling and stir down being up to 0 ℃ by force of pH5.5, and wash, separablely from filtrate go out title compound with ethyl acetate/tetrahydrofuran (THF) (8: 2) extraction with concentrated sodium chloride.Because the danger that forms disulphide is arranged, and the sylvite in this filtrate (3-amino-2-mercapto phenyl formic-potassium benzoate) preferably and then directly reacts.
Embodiment 2: phendioxin, 2,3-thiadiazoles-7-carboxylic acid
In top temperature is filtering solution 31.6 milliliters of vitriol oil acidifyings in addition of 0 ℃ of benzoic sylvite of 3-amino-2-mercapto phenyl formic that obtains to the said hydrolyzed by 17.6 mmole 2-aminobenzothiazole-7-carboxylate methyl esters in nitrogen atmosphere, and under fully stirring and cooling off by force, be 10 ℃ and be lower than the solution of 1.28 gram (18.6 mmole) Sodium Nitrites of dropping below the liquid level in 3.4 ml waters in top temperature, stirred this mixture then 4 hours, and made temperature rise to about 25 ℃.The throw out that elimination forms and with the frozen water washing with handle in tetrahydrofuran (THF) after activated carbon treatment, filters this mixture on a small amount of silica gel.Evaporate that to obtain 2.64 grams (88% two steps reaction back) fusing point after this filtrate be 232-233 ℃ thick title compound.The content of the title compound of HPLC (high pressure liquid chromatography) analysis revealed at least 83% and about 8-17% isomer phendioxin, 2,3-thiadiazoles-5-carboxylic acid.To obtain fusing point be 239-240 ℃ pure title compound to recrystallization in dioxan.
Embodiment 3: phendioxin, 2,3-thiadiazoles-7-carbonyl chlorine
With 290 gram phendioxins, 2,3-thiadiazoles-7-carboxylic acid is suspended in 1.6 liters of toluene, adds 3.5 milliliters of dimethyl formamides and 129 milliliters of thionyl chloride, and stirs this mixture down at 80-90 ℃, and along with the carrying out that discharges gas, this suspension changes solution into.When reaction finished, solution was cooled and filters on small amount of H yflo, with toluene wash resistates and evaporated filtrate, obtained the further thick acyl chlorides of direct reaction of 297 grams (93%).
Embodiment 4: phendioxin, 2,3-thiadiazoles-7-thiocarboxylic acid-S-methyl esters
In the solution of 1450 milliliters of methylene dichloride, adding 210 milliliters of triethylamines and 2.1 gram 4-Dimethylamino pyridines to 60.7 gram (1.26 moles) methyl mercaptans under 0 ℃.0 to 5 ℃ of down cooling, drip simultaneously 250.1 gram (1.26 moles) above-mentioned acyl chlorides be dissolved in 1.2 liters in the methylene dichloride solution and at room temperature stirred subsequently 3 hours.Add frozen water then, use the dichloromethane extraction water, wash the organic extract liquid of merging with water, use dried over sodium sulfate, dry and evaporation on a small amount of silica gel.Retaining 236 gram (89%) fusing points is 132-134 ℃ phendioxin, 2, and 3-thiadiazoles-7-thiocarboxylic acid-S-methyl esters.
Embodiment 5:3-Methyl anthranilate:
When stirring, in being cooled to-5 ℃ 500 ml methanol, drip 130 milliliters of (1.78 moles) thionyl chloride, and fully stirred this mixture 15 minutes down at 0 ℃.Under same temperature, add 70 gram (0.5 mole) solid 3-benzaminic acid then, stirred this mixture 15 minutes and heating, under 70 ℃, make the solution incubated overnight of formation.Evaporation then adds ethyl acetate and frozen water and adds saturated solution of sodium bicarbonate that to make the pH value be 7.5 in resistates.With this product of ethyl acetate extraction and wash extract with water, with dried over sodium sulfate and evaporation.Obtain crystalline oily 69.8 gram (92.2%) pure methyl ester when static, fusing point 37-38 ℃.
Embodiment 6:3-thioureido methyl benzoate:
Earlier 11.3 gram 3-Methyl anthranilates are added in the reaction vessel as being dissolved in 75 milliliters of solution in the chlorobenzene, under-5-0 ℃, in 15 minutes, drip 2.07 milliliters of vitriol oils (96%), continue to stir 5 minutes, and added 6.8 gram Sodium Thiocyanate 99s and this mixture of restir under 0 ℃ 15 minutes being up to then in batches.Add 0.2 milliliter of 15-hat-5 then, be 100 ℃ and stirred this mixture 10 hours down bathing temperature, cool off and throw out that elimination forms and washing with water 3 times.Obtaining 13.5 gram (85.9%) fusing points is 171-172 ℃ title compound.
Embodiment 7:2-aminobenzothiazole-7-carboxylate methyl ester:
8.4 gram 3-thioureido methyl benzoate are suspended in 120 milliliters of chlorobenzenes, under 0 ℃, in 1 hour, add 2.2 milliliters of bromines that are dissolved in 30 milliliters of chlorobenzenes, stir as far as possible fully simultaneously, under room temperature, stir then.Be incubated 4 hours down at 70 ℃ again,, add a small amount of ether and leach throw out,, filter once more and wash with water with 70 milliliters of sodium bicarbonate aqueous solution thorough mixing with postcooling.Obtaining 7.7 gram (88%) fusing points is 231-232 ℃ crude product.The HPLC analysis revealed contains pure title compound and 8-18% isomery 2-aminobenzothiazole-5-carboxylate methyl ester more than 83%.Make its suspension and 70 ℃ of down of short duration heating with ethyl acetate, be cooled to 30 ℃ and filter and obtain pure title compound, fusing point＞250 ℃.
If at acetate, rather than carry out this reaction in chlorobenzene, undesirable isomer 2-amino-benzothiazole-5-carboxylate methyl ester content only is about 5%.
Embodiment 8: directly prepare phendioxin with 2-aminobenzothiazole-7-carboxylate methyl ester, and 2, the method for 3-thiadiazoles-7-carboxylic acid
1.3 kilogram 2-aminobenzothiazole-7-carboxylate methyl ester kept 4 hours in 3.5 kilograms of KOH50% down in 120 ℃/1-2 crust, then under 0-5 ℃ with aqueous hydrochloric acid this mixture that neutralizes.Under 0 to 10 ℃, in this solution, be metered into 40% sodium nitrite in aqueous solution and leach settled product, washing and dry: 1.03 kilograms of phendioxins, 2,3-thiadiazoles-7-carboxylic acid, fusing point 230-233 ℃ (theoretical value of two-step reaction 91%).
Embodiment 9: directly prepare phendioxin with 2-methylamino benzo thiazole-7-carboxylic acid, and 2, the method for 3-thiadiazoles-7-carboxylic acid
In an autoclave, the suspension (92.7%) of 150 gram 2-methylamino benzo thiazole-7-carboxylic acids and 596 gram 47%KOH are remained on 155 ℃ of 1.7-1.8 and clung under the conditions 12 hours, then 20-25 ℃ of following filtering separation.In 635 grams, 37% hydrochloric acid, drip this filtrate and add 50 ml methanol.In this suspension, dripping 200 gram 30% sodium nitrite in aqueous solution under-10 ℃ to-5 ℃ and this mixture was fully reacted 2 hours.It is 260-262 ℃ thick phendioxin that suction strainer and washing obtain 112 gram fusing points, 2, and 3-thiadiazoles-7-carboxylic acid.HPLC analysis revealed content is the pure title compound of 90-93%.
The benzoic preparation of embodiment 10:3-amino-2-mercapto phenyl formic
When stirring under the nitrogen atmosphere, in 3.4 grams, 50% potassium hydroxide solution, add 1.3 gram 2-amino-7-methoxycarbonyl methyl benzoate, and this mixture was kept 12 hours.Cool off, under inert atmosphere, add again 1.3 grams, 50% potassium hydroxide solution then, and under 150 ℃, this mixture was kept 4 hours again.Cooling off and make the pH value to wherein dripping a small amount of sulfuric acid in inert atmosphere under 0 ℃ then is 5.5.Leach the throw out of formation, and wash with frozen water.Under high vacuum, obtain fusing point after the drying and be 255-258 ℃ title compound, contain the disulphide (based on mass spectroscopy) of trace correspondence.
Embodiment 11:3-(N '-the methylthiourea base) benzoic preparation
279.6 gram 3-benzaminic acid, 164.1 gram Trapexs and 1000 are restrained the mixture heating up of 100% acetate to 80-85 ℃.Temperature rises to 95-100 ℃ and do not need further heating in 20 minutes, and the clear liquid that has product therefrom slowly to crystallize out forms.Down kept suspension 2 hours at 90-100 ℃, be cooled to 15-20 ℃ subsequently, suction strainer and with the material on the acetate washing suction filter.Obtain 404 gram title compounds, purity 99.5%, is decomposed by fusing point: 190-191 ℃.Productive rate: be 95.7% of theoretical value.
The preparation of embodiment 12:2-methylamino benzo thiazole-7-carboxylic acid
In 2 hours the drips of solution of 163 gram bromines and 50 grams, 100% acetate being added to 212 gram 3-(N '-methylthiourea base) phenylformic acid and 500 under 45-50 ℃ restrains in the suspension of 100% acetate.In 2.5 hours, this mixture heating up is also continued to react 2 hours till gas release finishes to 90-100 ℃ then.In decompression down and 80-85 ℃ steam acetate 150 grams after, add water 200 and restrain, and drip 30% sodium hydroxide solution, the pH value that makes this mixture is 2.Obtain 179.2 gram title compounds in 70-80 ℃ of following suction strainer and washing, fusing point＞330 ℃.The HPLC analysis revealed contains this title compound 94.6%, and all the other are 3-4% isomery 2-methylamino-benzothiazole-5-carboxylic acid.
Productive rate: be 81.5% of theoretical value.
Embodiment 13:2-methylamino-benzothiazole-7-carboxylic acid is without the preparation (still reaction) of isolation of intermediate products
In the solution that in 50 minutes, in the suspension of 70 gram 3-benzaminic acid and 250 grams, 100% acetate, drips 39.2 gram Trapexs and 50 grams, 100% acetate under 75-80 ℃.Temporary transient a kind of therefrom 3-(N '-methylthiourea base) phenylformic acid that forms is slowly with the sedimentary solution of crystallized form.After making this mixture fully react 2 hours, be cooled to 50 ℃, and at the solution that in 2 hours, drips 81.5 gram bromines and 50 grams, 100% acetate under 45-50 ℃.Then in 2 hours with this mixture heating up to 90-100 ℃, and it was fully reacted 2 hours, finish until gas release.After steaming 160 gram acetate under the 75-80 ℃ of decompression, in resistates, add 200 gram water, drip 67 grams, 30% sodium hydroxide solution, at 75-80 ℃ of this mixture of following suction strainer, and wash resistates with water, obtain the product of 73 gram fusing point＞330 ℃.The HPLC analysis revealed contains title compound 97%, and 0.7% isomery 2-methylamino benzo thiazole-5-carboxylic acid.Productive rate: be 68% of theoretical value.
Embodiment 14:3-amino-2-mercapto phenyl formic methyl benzoate
Go up hydrogenation 1 gram phendioxin under 160 ℃ of first pressing, 150 crust conditions, 2, the solution of 3-thiadiazoles-7-carboxylate methyl ester in 40 milliliters of dioxan at 0.5 gram palladium charcoal (5%).After the starting material complete reaction, leach catalyzer, with the dioxan washing, evaporated filtrate is avoided ingress of air, and the resistates of purifying on silica gel (hexane/ethyl acetate (6: 4)).Obtaining fusing point by this technology is 174-175 ℃ title compound.
Can be by the compound of enumerating in the table below the preparation of the similarity method described in these embodiment.
Table 1: following formula: compound
Compound (X)
nZ physical data/fusing point
1.1 4-F COOCH
3
1.2 5-F COOCH
3
1.3 6-F COOCH
3125-127 ℃ (disulphide)
1.4 4,6-two-F COOCH
3
1.5 4,5-two-F COOCH
3
1.6 5,6-two-F COOCH
3
1.7 4,5,6-three-F COOCH
3
1.8 H COOCH
3 174-175℃
1.9 H COOC
2H
5
1.10 H COOC
3H
7-n
1.11 H COOC
3H
7-i
1.12 H COOC
6H1
3-n
1.13 4-F COOC
2H
5
1.14 6-F COOC
2H
5
1.15 5-F COOC
2H
5
1.16 H COSCH
3
1.17 H CN
1.18 H COOH 255-258℃
1.19 4-F COOH
1.20 5-F COOH
1.21 6-F COOH
1.22 4,6-two-F COOH
1.23 4,5,6-three-F COOH
1.24 5-F CN
1.25 H COO-K
+
Table 2: following formula: compound
Compound (X)
nZ T physical data
2.1 4-F COOCH
3263-264 ℃ of H fusing point
2.2 5-F COOCH
3 H
2.3 6-F COOCH
3 H
2.4 4,6-two-F COOCH
3H
2.5 4,5-two-F COOCH
3H
2.6 5,6-two-F COOCH
3H
2.7 4,5,6-three-F COOCH
3H
2.8 H COOCH
3H fusing point＞250 ℃
2.9 H COOC
2H
5 CH
3
2.10 H COOC
3H
7-n the tertiary butyl
2.11 H COOC
3H
7-i H
2.12 H COOC
6H
13-n H
2.13 4-F COOC
2H
5 H
2.14 6-F COOC
2H
5 H
2.15 5-F COOC
2H
5 H
2.16 H COSCH
3 H
2.17 4-F COSCH
3 H
2.18 H COOH CH
3Fusing point＞330 ℃
2.19 H COOH C
2H
5
2.20 H COOH sec.-propyl
2.21 6-F COOH CH
3
2.22 H COOH benzyl
2.23 4,5,6-three-F COOH H
2.24 5-F CN H
2.25 H CN H
Table 3: following formula: compound
Compound (X)
nThe Z physical data
3.1 4-F COOCH
3Fusing point 133-134 ℃
3.2 5-F COOCH
3
3.3 6-F COOCH
3Fusing point 122-125 ℃
3.4 4,6-two-F COOCH
3
3.5 4,5-two-F COOCH
3
3.6 5,6-two-F COOCH
3
3.7 4,5,6-three-F COOCH
3
3.8 H COOCH
3
3.9 H COOC
2H
5
3.10 H COOC
3H
7-n
3.11 H COOC
3H
7-i
3.12 H COOC
6H
13-n
3.13 4-F COOC
2H
5
3.14 6-F COOC
2H
5
3.15 5-F COOC
2H
5
3.16 H COSCH
3Fusing point 131-132 ℃
3.17 4-F COSCH
3Fusing point 138-140 ℃
3.18 232-233 ℃ of H COOH fusing point
3.19 224-226 ℃ of 4-F COOH fusing point
3.20 232-235 ℃ of 5-F COOH fusing point
3.21 222-223 ℃ of 6-F COOH fusing point
3.22 4,6-two-F COOH
3.23 4,5,6-three-F COOH
3.24 5-F CN
3.25 75-78 ℃ of 4-F CO-C1 fusing point
Table 4: following formula: compound
Compound (X)
nZ T physical data
4.1 4-F COOCH
3163-165 ℃ of H fusing point
4.2 5-F COOCH
3 H
4.3 6-F COOCH
3 H
4.4 4,6-two-F COOCH
3H
4.5 4,5-two-F COOCH
3H
4.6 5,6-two-F COOCH
3H
4.7 4,5,6-three-F COOCH
3H
4.8 H COOCH
3171-172 ℃ of H fusing point
4.9 H COOC
2H
5 H
4.10 H COOC
3H
7-n CH
3
4.11 H COOC
3H
7-i the tertiary butyl
4.12 H COOC
6H
13-n H
4.13 4-F COOC
2H
5 H
4.14 6-F COOC
2H
5 H
4.15 5-F COOC
2H
5 H
4.16 H COSCH
3 H
4.17 4-F COSCH
3 H
4.18 H COOH CH
3Fusing point 190-191 ℃
4.19 4-F COOH CH
3
4.20 5-F COOH C
2H
5
4.21 6-F COOH sec.-propyl
4.22 4,6-two-F COOH CH
3
4.23 4,5,6-three-F COOH benzyl
4.24 5-F CN H
4.25 H CHO H
Table 5: formula VI compound
Compounds X Z Hal physical data
5.1 H COOH Cl ＞250℃
5.2 H COOCH
3 Cl
5.3 H COOC
2H
5 Cl
5.4 H COCl Cl
5.5 H CHO Cl
5.6 H COOH F
5.7 6-F COOH F
5.8 6-F COCl Cl
5.9 H COOC
3H
7-n Cl
5.10 6-Br COOH Br
5.11 H COSCH
3 Cl
5.12 H COSC
2H
5 Cl
5.13 H CN Cl
5.14 6-Cl COOH Cl
5.15 6-F CN F
5.16 4-F COOH Cl
5.17 5-F COOCH
3 Cl
5.18 4,6-two-F COOCH
3Cl
5.19 4,5,6-three-F COOH Cl
5.20 6-Br COOCH
3 Cl
5.21 H COOCH
3 ClO
4
5.22 H COOH ClO
4
5.23 H COOH BF
4
Table 6: formula VII compound
Compounds X Z physical data
6.1 H COOH ＞290℃
6.2 H COOCH
3
6.3 H COOC
2H
5
6.4 H COCl
6.5 H CHO
6.6 H COOH
6.7 6-F COOH
6.8 6-F COCl
6.9 H COOC
3H
7-n
6.10 6-Br COOH
6.11 H COSCH
3
6.12 H COSC
2H
5
6.13 H CN
6.14 6-Cl COOH
6.15 6-F CN
6.16 4-F COOH
6.17 5-F COOCH
3
6.18 4,6-two-F COOCH
3
6.19 4,5,6-three-F COOH
6.20 6-Br COOCH
3
Claims (9)
1. the method for preparing the formula III compound:
In the formula
X is a halogen,
N is 0,1,2 or 3;
Z is CN, CO-A or CS-A,
A is hydrogen, halogen, OR
1, SR
2Or N (R
3) R
4
R
1To R
4Be hydrogen, contain the replacement or the saturated or unsaturated alkyl of non-replacement open chain that are no more than 8 carbon atoms,
This method comprises and changes following formula I a compound into formula I compound
X and n define as formula III in the formula,
X, n and Z define as formula III in the formula,
With by further reacting with nitrous acid or an organic or inorganic nitrite and the formula I compound that obtains thus, make the formula III compound.
2. the process of claim 1 wherein formula Ia compound and halogenating agent the reaction make formula I compound, Z is that CO-A and A are halogens in the formula.
3. the method for claim 2, wherein halogenating agent is SOCl
2Or COCl
2
4. the process of claim 1 wherein that compound and formula M-A compound that claim 2 or 3 obtains react, M is a halogen in the formula, Li
+, Na
+, K
+, 1/2Mg
2+Or quaternary ammonium ion, the definition of A such as formula III but except that halogen, obtain the formula III compound, Z is COA in the formula.
5. the process of claim 1 wherein that Z is compound and the vulcanizing agent reaction of CO-A in the formula that claim 4 obtains, make formula III wherein Z be the compound of CS-A.
6. the method for claim 5, wherein vulcanizing agent is thiophosphoric anhydride or 4-p-methoxy-phenyl phosphine sulfide acid epidithio acid anhydride.
7. the process of claim 1 wherein compound that claim 2 or 3 obtains and ammonia react obtain formula III wherein Z be that CO-A and A are NH
2Compound.
8. the process of claim 1 wherein the reaction of compound that claim 7 obtains and dewatering agent make formula I wherein Z be the compound of CN.
9. the process of claim 1 wherein the reaction of compound that claim 2 or 3 obtains and reductive agent, make formula III wherein Z be that CO-A and A are the compounds of hydrogen.
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| KR20070007759A (en) * | 2003-07-10 | 2007-01-16 | 아칠리온 파르마세우티칼스 인코포레이티드 | Substituted arylthiourea derivatives useful as inhibitors of viral replication |
| CA2560741C (en) | 2004-03-25 | 2013-08-06 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof |
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|---|---|---|---|---|
| US4150140A (en) * | 1976-12-23 | 1979-04-17 | The Upjohn Company | Benzothiazolyl oxanic acids, esters and salts |
| DE2757924A1 (en) * | 1977-12-24 | 1979-07-05 | Hoechst Ag | PROCESS FOR THE PRODUCTION OF VINYL CHLORIDE POLYMERIZES |
| DE3601286A1 (en) * | 1986-01-17 | 1987-07-23 | Consiglio Nazionale Ricerche | COLLECTING AGENTS FOR THE SELECTIVE FLOTATION OF LEAD AND ZINC PLUGS AND METHOD FOR THE PRODUCTION THEREOF |
| DE19775050I2 (en) * | 1987-08-21 | 2010-12-16 | Syngenta Participations Ag | Benzothiadiazoles and their use in processes and agents for plant diseases. |
| DE59003043D1 (en) * | 1989-02-21 | 1993-11-18 | Ciba Geigy | Means for protecting plants against diseases. |
| EP0529600B1 (en) | 1991-08-30 | 1996-11-06 | Hoechst Aktiengesellschaft | Process for the preparation of 2-aminobenzothiazoles |
| JPH0690518A (en) * | 1992-09-09 | 1994-03-29 | Toshiba Corp | Ground relay |
| JP3310104B2 (en) * | 1994-04-04 | 2002-07-29 | 三新化学工業株式会社 | Method for producing 2-aminothiophenols |
| BR9509373A (en) * | 1994-10-17 | 1998-07-07 | Novartis Ag | Process for the preparation of substituted 3-aminobenzonitriles |
-
1996
- 1996-12-12 IL IL13390096A patent/IL133900A/en not_active IP Right Cessation
- 1996-12-12 DK DK96810865T patent/DK0780372T3/en active
- 1996-12-12 DE DE69616956.8T patent/DE69616956T3/en not_active Expired - Lifetime
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- 1996-12-12 AT AT96810865T patent/ATE208760T1/en active
- 1996-12-12 EP EP96810865.4A patent/EP0780372B3/en not_active Expired - Lifetime
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- 1996-12-12 IL IL11981996A patent/IL119819A/en not_active IP Right Cessation
- 1996-12-19 SK SK1636-96A patent/SK283840B6/en not_active IP Right Cessation
- 1996-12-19 PL PL96317601A patent/PL187885B1/en unknown
- 1996-12-19 MX MXPA02000515A patent/MXPA02000515A/en active IP Right Grant
- 1996-12-19 HU HU9603527A patent/HU221600B/en not_active IP Right Cessation
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- 1996-12-19 MX MX9606665A patent/MX9606665A/en unknown
- 1996-12-19 CZ CZ19963773A patent/CZ291857B6/en not_active IP Right Cessation
- 1996-12-19 CA CA002193460A patent/CA2193460C/en not_active Expired - Fee Related
- 1996-12-20 RU RU96124374/04A patent/RU2176241C2/en not_active IP Right Cessation
- 1996-12-20 AU AU76404/96A patent/AU713526B2/en not_active Ceased
- 1996-12-20 US US08/770,353 patent/US5770758A/en not_active Expired - Lifetime
- 1996-12-20 CN CNB001316702A patent/CN1163491C/en not_active Expired - Lifetime
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- 1996-12-20 JP JP35519496A patent/JP4217924B2/en not_active Expired - Lifetime
- 1996-12-20 CN CN96117901A patent/CN1078888C/en not_active Expired - Lifetime
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2000
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2004
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